PROJECT SUMMARY Dr. Sahib Khalsa is applying for the Mentored Patient-Oriented Career Development Award (K23) to support his growth as an independent researcher to delineate the pathophysiology of interoception (the brain body connection) in eating disorders. Anorexia nervosa (AN) is two to three-times deadlier than schizophrenia, bipolar disorder, and unipolar depression, yet the underlying pathophysiology and associated neural dysfunctions are poorly understood. Anticipating eating a meal makes individuals with AN fearful, which induces a state of Biased Interoceptive Anticipatory Signaling (BIAS) marked by a discrepancy between the actual interoceptive state and the subjective interoceptive experience. BIAS interferes with AN patients' ability to accurately sense what is happening in their bodies, which in turn reinforces fears of eating, food avoidance behaviors, and weight loss. To determine the neural basis of BIAS in AN, the candidate has developed a protocol that employs (a) interoceptive modulation using isoproterenol, a rapid peripherally acting sympathomimetic drug akin to adrenaline, (b) direct experimental manipulation of meal anticipation, which heightens anxiety in AN, and (c) functional magnetic resonance imaging to examine the brain's response to these manipulations. Weight-restored individuals with AN (to avoid the potentially confounding effects of starvation on measures of brain function) and sex and BMI matched healthy comparisons will undergo multi- level assessments focused on the negative valence domain and interoception. This proposal investigates the basic question ?how does the state of anticipating a meal induce fear and dysregulate the processing of body- relevant information in AN?? Addressing it will help to clarify the behavioral and brain processes that reinforce starvation in the presence of food availability, and will enable the development of specific food-focused fear extinction procedures. Dr. Khalsa's long-term career goal is to understand the neural sources of interoceptive dysregulation in eating disorders, and to develop novel treatments. The proposed research will accomplish first steps towards this goal by evaluating the role of interoception across levels of behavior, physiology and neural circuits in AN. The training activities of this project will allow Dr. Khalsa to develop expertise in pharmacological fMRI methodology, increased knowledge of advanced statistics, and enhanced expertise in eating disorder treatment. Dr. Khalsa has assembled a team of mentors uniquely suited to provide the required diversity of expertise. Dr. Paulus (LIBR Scientific Director and primary mentor) will provide expertise in psychiatric and pharmacological neuroimaging using interoceptive probes. Dr. Walter Kaye will provide mentorship in AN neurobiology and treatment. Dr. Jerzy Bodurka, LIBR Neuroimaging Core Director, will provide mentorship in fMRI data processing and structural/functional connectivity analyses. Dr. Danny JJ Wang will provide mentorship in perfusion MRI and the combination of pharmaco-imaging with ASL. The training and associated research will take place at LIBR, a psychiatric research institute with state-of-the-art neuroimaging facilities.